The β cell loss that leads to diabetes is silent. In type 1 diabetes mellitus (T1D), killing of β cells and subsequent presentation with hyperglycemia takes weeks in the nonobese diabetic (NOD) mouse model of T1D and possibly years in humans (Akirav et al., 2008, Diabetes 57:2883-2888). Hyperglycemia occurs when the majority of β cells have been destroyed, providing only limited options for therapy (Bluestone et al., 2010, Nature 464:1293-1300; Waldron-Lynch et al., 2009, Endocrinol. Metab. Clin. North Am. 38:303-317). Early detection of ongoing β cell death would allow for earlier interventions at a time before the development of hyperglycemia, when a more significant β cell mass is present. Indeed, immunotherapy is most successful in patients with residual β cell function (Waldron-Lynch et al., 2009, Endocrinol. Metab. Clin. North Am. 38:303-317; Bougneres et al., 1988, N. Engl. J. Med. 318:663-670; Keymeulen et al., 2005, N. Engl. J. Med. 352:2598-2608).
Measurements of insulin, proinsulin, and C-peptide responses to a variety of tests have been used as indices for β cell mass and destruction (Ludvigsson et al., 1982, Acta Diabetol. Lat. 19:351-358; Snorgaard et al., 1992, Diabetes Care 15:1009-1013; Greenbaum ct al., 2008, Diabetes Care 31:1966-1971; Steele et al., 2004, Diabetes 53:426-423), whereas HLA genes and autoantibodies have been used as genetic indicators of high-risk individuals (Erlich et al, 2008, Diabetes 57:1084-1092; Hagopian et al., 1995, J. Clin. Invest. 95:1505-1511; Verge et al., 1996, Diabetes 45:926-933). However; these measurements do not identify the ongoing β cell destruction in islets. Unfortunately, the first direct evidence of β cell destruction becomes apparent only after β cell function has been compromised and glucose levels have risen in response to provocative stimuli or a failure of β cells to respond to increased metabolic demand and insulin resistance (Sherr et al., 2008, Nat. Clin. Pract. Endocrinol. Metab. 4:334-343; Sosenko et al., 2007, Diabetes Care 30:38-42; Polonsky et al., 1988, New Eng. J. Med. 318: 1231-9). Furthermore, the location of the pancreas in the abdominal cavity and the relatively small size of the islets of Langerhans pose a significant limitation for direct islet imaging and evaluation of β cell mass (Medarova et al., 2008, Magn. Reson. Med. 59:712-720).
Epigenetic modifications of DNA are used by various cell types to control tissue-specific gene expression. These modifications include histone acetylation/deacetylation and DNA methylation (Klose et al., 2006, Trends Biochem. Sci. 31:89-97; Bartke et al., 2010, Cell 143:470-484; Wang et al., 2007, Trends Mol. Med. 13:373-380). Methylation of DNA sequences occurs in CpG dinucleotide sites to maintain a transcriptionally repressive chromatin configuration, whereas demethylation results in a transcriptionally permissive configuration (Miranda et al., 2007, J. Cell Physiol. 213:384-390). Differential methylation of oncogenes has been used to identify microsatellite instability in patients with colon cancer, and detection of differentially methylated DNA in the serum of cancer patients has been used as a biomarker for cancer diagnosis (Grady et al., 2001, Cancer Res. 61:900-902; Wallner et al., 2006, Clin Cancer Res. 12:7347-7352; Müller et al., 2003, Cancer Res. 63:7641-7645). Previous studies have relied on the detection of serum-derived tissue-specific epigenetic modifications to identify DNA released from those cells when they die.
There is a great need in the art for compositions and methods for monitoring β cell destruction in individuals having, or at risk of developing, diabetes. The present invention addresses these needs in the art.